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A Look Back: The Best of 2012
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What Is Propofol — and How Could It Have Killed Michael Jackson?
by Katherine Harmon
In the first week of the trial of Conrad Murray, Michael Jackson's physician, Los Angeles jurors heard audio recordings of the late pop star's slurred speech, in addition to the litany of prescription drugs he had taken in the hours and weeks prior to his June 25, 2009, death.
It will be up to them to decide if they agree with the Los Angeles County coroner's office, which labeled Jackson's death a homicide.
According to the 2009 autopsy report, "the cause of death is acute propofol intoxication," which caused the singer to stop breathing. In addition to propofol (a hypnotic drug used for general anesthesia, sedation and in veterinary medicine) the examiner also found traces of lorazepam (a benzodiazepine drug used to treat anxiety and insomnia); midazolam (another benzodiazepine, indicated for insomnia and medical sedation); lidocaine (a local anesthetic often included with propofol to relieve injection pain); diazepam (a benzodiazepine to treat anxiety, insomnia and alcohol withdrawal); and nordiazepam (a benzodiazepine-derived sedative, often used to treat anxiety) in Jackson's bloodstream.
To support the weighty pronouncement of homicide, the medical examiner concluded that: "circumstances indicate that propofol and the benzodiazepines were administered by another. The propofol was administered in a nonhospital setting without any appropriate medical indication. The standard of care for administering porpofol was not met."
Prosecutors are following this line of evidence, arguing that Murray should be held responsible for Jackson's death because he lacked adequate justification, expertise and equipment for giving this powerful drug to his client (who was reportedly aiming to stay rested in preparation for a comeback tour). Although Murray was using a device to keep tabs on Jackson's vitals, as is recommended while using a general anesthetic, the fingertip pulse and blood-oxygen monitor he used is "specifically labeled against continuous monitoring," said an executive from Nonin Medical, Inc., which makes the $275 device, CNN reported. And according to testimony from a paramedic that responded to the 911 call and found Jackson without a pulse, Murray did not mention giving Jackson anything other than the lorazepam.
Given Jackson's apparently substantial admixture of meds and oft-discussed medical conditions, why was propofol the most likely candidate for his death — and can it be used more safely? To find out, Scientific American spoke with Beverly Philip, a professor of anesthesia at Harvard Medical School.
[An edited transcript of the interview follows.]
Propofol is not your run-of-the-mill sleeping aid. How does it differ from more commonly used sedatives?
It's not a sleeping aid at all. What it is is a general anesthetic. This puts people into general anesthesia — a sleeping aid doesn't do that.
This is not meant to be used at home. This is meant to be used by anesthesiologists in a clinical setting. So the use as a sleep aid is way off the mark.
How does propofol work in the body?
We don't know exactly how general anesthesia works. This works as other general anesthetics work, acting on receptors in the brain — possibly the GABA [gamma-aminobutyric acid] receptors, because that is a mechanism for a lot of sleepiness in the brain.
Are there negative side effects that propofol can have — even when it is used as directed and in a proper setting?
Yes. Unlike other sedatives, this drug has an extraordinarily narrow safety margin. It changes the body's state very rapidly so that the patient will go unconscious and stop breathing. It can affect the breathing even before unconsciousness. So even in trained hands, it is very difficult to titrate just where you want. We can do it, but that's what we're trained and educated to do — it's not easy. If I'm inducing anesthesia, it will act inside of 60 seconds.
So as a cardiologist and personal physician to Michael Jackson, is it likely that Conrad Murray did not have the proper training to administer this type of drug safely?
I have heard nothing about how he had had training to use the drug. How it was used here, we call it recreational use. This had nothing to do with the medical care of a patient, which is a situation in which you have things to make it safe, so it's not even in the ballpark of normal use.
The drug also has some reportedly pleasant side effects, such as euphoria. Is that common among sedatives?
When it first came out it was very obvious that it causes euphoria. It's not that dissimilar to alcohol. It reduces inhibition, people get giddy, and whatever thoughts they have on their mind, they tell you. It can also cause hallucinations, because whatever is in a person's head is more likely to be seen. We see it as they go off to sleep and as they wake up.
Recreationally, a lot of people die from this. It's very difficult to administer safely even in the most controlled settings.
The FDA [U.S. Food and Drug Administration] is in the process of making this a restricted drug, recognizing its euphoric property.
Are there other anesthetics that are used off-label as sleep aids?
There are other things that are quite in a different class. For example, Valium and its cousins: In very, very high doses, someone could sleep, but you have to give lots of it, and it works very slowly to cause sleep.
Drugs in the Valium class and painkillers have a reversing agent that's commercially available. There's no reversing agent for propofol.
The coroner's reports from Michael Jackson's autopsy also found evidence that he was on other drugs at the time he died, including lidocaine, lorazepam and diazepam. Is it possible Jackson's death was due to a reaction from these drugs or do you think propofol alone could have killed him?
There's quite a sufficient answer just with this drug alone. But as with any other intoxicant, when you've taken any other drug, they all add up — and propofol is no different.
The fact that there's no reversing agent, and the ability to pull someone out of it — which we call rescuing — requires considerable professional training.
This is not a sleeping aid. This is a general anesthetic drug. Everyone has been saying, "Michael Jackson wanted to be asleep." No one talked about relaxing drugs. With this drug in unskilled hands, this sleep was permanent. It induces general anesthesia, which is not like a night's sleep.
--Originally published, Scientific American online, October 3, 2011.
Ban Chimp Testing by the Editors
The testing began shortly after Bobby's first birthday. By the time he was 19 he had been anesthetized more than 250 times and undergone innumerable biopsies in the name of science. Much of the time he lived alone in a cramped, barren cage. Bobby grew depressed and emaciated and began biting his own arm, leaving permanent scars.
Bobby is a chimpanzee. Born in captivity to parents who were also lab chimps, he grew up at the Coulston Foundation, a biomedical research facility in Alamogordo, N.M., that was cited for repeated violations of the Animal Welfare Act before it was shuttered in 2002. He is one of the lucky ones. Today he lives in a sanctuary called Save the Chimps in Fort Pierce, Fla., where he can socialize and roam freely. Last year the National Institutes of Health announced plans to put some 180 ex-Coulston chimps currently housed at the Alamogordo Primate Facility back in service, to rejoin the roughly 800 other chimps that serve as subjects for studies of human diseases, therapies and vaccines in the U.S., which is the only country apart from Gabon to maintain chimps for this purpose.
Public opposition is on the rise. In April a bipartisan group of senators introduced a bill, the Great Ape Protection and Cost Savings Act, to prohibit invasive research on great apes, including chimps. And when the NIH announced its plans for bringing the Alamogordo chimps out of retirement, objections from the Humane Society, primatologist Jane Goodall and others prompted the agency to put the plans on hold until the Institute of Medicine (IOM) completes a study of whether chimps are truly necessary for biomedical and behavioral research. The IOM project itself has been criticized: the NIH instructed it to omit ethics from consideration.
In April, McClatchy Newspapers ran a special report based on its review of thousands of medical records detailing research on chimps like Bobby. The stories painted a grim picture of life in the lab, noting disturbing psychological responses in the chimps. Then, in June, Hope R. Ferdowsian of George Washington University and her colleagues reported in PLoS ONE that chimps that had previously suffered traumatic events, including experimentation, exhibit clusters of symptoms similar to depression and post-traumatic stress disorder in humans.
That chimps and humans react to trauma in a like manner should not come as a surprise. Chimps are our closest living relatives and share a capacity for emotion, including fear, anxiety, grief and rage.
Testing on chimps has been a huge boon for humans in the past, contributing to the discovery of hepatitis C and vaccines against polio and hepatitis B, among other advances. Whether it will continue to bear fruit is less certain. Alternatives are emerging, including ones that rely on computer modeling and isolated cells. In 2008 pharmaceutical manufacturer GlaxoSmithKline announced it would end its use of chimps.
In our view, the time has come to end biomedical experimentation on chimpanzees. The Senate bill would phase out invasive research on chimps over a three-year period, giving the researchers time to implement alternatives, after which the animals would be retired to sanctuaries.
We accept that others may make a different moral trade-off. If the U.S. elects to continue testing on chimps, however, then it needs to adopt stricter guidelines. Chimps should be used only in studies of major diseases and only when there is no other option. Highly social by nature, they should live with other chimps and in a stimulating environment with room to move around. And when a test inflicts pain or psychological distress, they should have access to treatment that eases those afflictions.
The Animal Welfare Act affords chimps some protection. But clearly more is needed. To develop and enforce tighter regulations, the U.S. Department of Agriculture, which enforces the Animal Welfare Act, should establish an ethics committee specifically for biomedical research on chimps. The committee would need to include not just medical researchers but also bioethicists and representatives from animal welfare groups. Such measures would no doubt make medical testing on chimps even more expensive than it already is. Yet if human lives are going to benefit from research on our primate cousins, it is incumbent on us to minimize their suffering, provide them with an acceptable quality of life — and develop techniques that hasten the day when all of Bobby's fellow chimps can join him in retirement.
--Originally published, Scientific American online, September 28, 2011.
Foods in the Year 2000 by Christina Agapakis
A lot of proposed synthetic biology applications can seem pretty out there, but some are really out there. NASA is currently advertising open postdoctoral positions in synthetic biology, with particular emphasis on food production in space. Engineered organisms have the potential to do lots of things that would be useful for space colonists, from producing food and fuel to treating wastewater. Because organisms replicate themselves, future astronauts would only have to bring some spores and seeds and empty bioreactors, the organisms would do the rest of the work.
I am fascinated by these proposals, and other proposals large and small for how biological engineering might someday impact the way that we produce, process, and prepare our food. The way we eat and the way we imagine the "food of the future" is really complicated, and has a long and interesting history tied not only to our culinary cultures and the science of nutrition, but often to the hot new science and technology of the day.
In the 1890's, that technology was synthetic chemistry, making it possible to generate organic chemicals from inorganic starting materials. New industries were springing up that replaced old agricultural methods with chemical ones, in particular the production of synthetic dyes and flavors. This led some chemists to speculate on how this technology would be used a hundred years in the future, extrapolating the current industrial transformations into nearly every organic arena. This speculative application of synthetic chemistry to food production is detailed in an 1894 article in McClure's Magazine by Henry J.W. Dam titled "Foods in the Year 2000: Professor Berthelot's Theory that Chemistry Will Displace Agriculture." By 2000, Marcellin Berthelot, considered to be one of the greatest chemists of all time, believed that we would no longer have agriculture, that instead:
The epicure of the future is to dine upon artificial meat, artificial flour, and artificial vegetables ... Wheat fields and corn fields are to disappear from the face of the earth, because flour and meal will no longer be grown, but made ... Coal will no longer be dug, except perhaps with the object of transforming it into bread or meat. The engines of the great food factories will be driven, not by artificial combustion, but by the underlying heat of the globe.
What would this food synthesized from coal with geothermal power look like? What would it taste like?
We shall give you the same identical food, however, chemically, digestively, and nutritively speaking. Its form will differ, because it will probably be a tablet. But it will be a tablet of any color and shape that is desired, and will, I think, entirely satisfy the epicurean senses of the future.
"Food pills" are a common theme in science fiction, especially for space travel where astronauts have to travel light, and it's interesting to see how that has transformed, with NASA now thinking beyond synthetic chemistry to synthetic biology. But it's the scientific language of Professor Berthelot that's particularly interesting to me:
In order to clearly conceive these impending changes, it must be remembered that milk, eggs, flour, meat, and indeed, all edibles, consist almost entirely (the percentage of other elements is very small) of carbon, hydrogen, oxygen, and nitrogen ... These four elements, universally existing, are destined to furnish all the food now grown by nature, through the rapid and steady advance of synthetic chemistry. Synthetic chemistry is the special science which takes the elements of a given compound, and induces them to combine and form that compound. It is thereverse of analytic chemistry, which takes a given compound, and dissociates and isolates its elements. Analytic chemistry would separate water intooxygen and hydrogen, and synthetic chemistry would take oxygen and hydrogen, mix them, put a match to the mixture, and thus form water. For many years past synthetic chemistry has had an eager eye upon food-making.
This analytic/synthetic transition is a narrative that has been adopted by synthetic biologists and it's interesting to see how closely the language today mirrors that of the early synthetic chemists. As we move from analysis to synthesis we can develop amazing technologies, but we often also learn just how complicated things are, how systems are greater than the sum of their parts. We can measure the nutritional needs of a human at a chemical, molecular level and we can likely survive off of biochemically balanced tablets for a while, but we also know that eating real foods made out of real plants and prepared into balanced meals is the healthiest way to eat. Beyond that, we're not just chemicals, we're people, and people like to eat. When we apply our technologies to our foods, we have to remember not just the balance of carbohydrates, proteins, fats, and vitamins, but the experience of eating. Hopefully as we speculate on food in the year 2100, synthetic biology will think beyond the food pill.
--Originally published, Scientific American online, March 31, 2012.
Timelines, Roadmaps, and Tools: Navigating the Futures of Synthetic Biology by Christina Agapakis
In the summer of 2012 I got a travel fellowship from the SynBERC Student & Postdoc Association and Practices Thrust to attend the Six Parties Symposium on Synthetic Biology. The theme of the symposium was "Synthetic Biology for the Next Generation" and was jointly run by the National Academies of Science and Engineering from the US, the UK, and China. The fellows were asked to write a short perspective about the symposium and how we see the field advancing in the future.
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